Metabotropic Glutamate Receptor and Fragile X Signaling in a Female Model of Escalated Aggression.
Metabotropic Glutamate Receptor and Fragile X Signaling in a Female Model of Escalated Aggression.
复制标题
代谢性谷氨酸受体和脆弱的X信号传导在女性的侵略性升级模型中。
DOI：
10.1016/j.biopsych.2015.07.021
复制
发表时间：
2016-04-15
影响因子：
10.6
通讯作者：
Meisel RL
中科院分区：
文献类型：
--
作者：
Been LE;Moore KM;Kennedy BC;Meisel RL
升级的攻击是许多精神疾病的行为标志，其特征是失去控制。神经生物学基础升级的侵略是未知的，特别是在女性研究不足。我们实验室的研究表明，雌性仓鼠重复的攻击性经历导致对未来攻击性遭遇的反应升级，以及NAc神经元树突棘密度增加。我们推测，通过脆性X智力迟钝蛋白（FMRP）通路激活I组代谢型谷氨酸受体信号可能是与攻击升级相关的突触可塑性的基础。雌性仓鼠在事先接受或未接受mGluR 5拮抗剂MPEP治疗的情况下每天进行5次攻击测试。在攻击性测试之后，测量PSD-95和SAPAP-3在丘脑核中的mRNA表达和蛋白水平，以及磷酸化FMRP的水平。雌性仓鼠中的攻击性的经验依赖性升级取决于mGluR 5受体的激活。此外，侵略性的经验减少了磷酸化的FMRP在NAc这是耦合到一个长期增加的表达的突触支架蛋白，PSD-95和SAPAP-3。最后，PSD-95的经验依赖性增加被mGluR 5受体的拮抗作用阻止。I组代谢型谷氨酸受体激活FMRP通路参与调节攻击性经历后的突触可塑性。NAc是治疗升级攻击的临床前研究的新靶点，其额外的好处是新兴的治疗方法可能有效治疗女性和男性的病理性攻击。
Escalated aggression is a behavioral sign of numerous psychiatric disorders characterized by a loss of control. The neurobiology underlying escalated aggression is unknown and is particularly understudied in females. Research in our laboratory demonstrated that repeated aggressive experience in female hamsters resulted in an escalated response to future aggressive encounters and an increase in dendritic spine density on NAc neurons. We hypothesized that the activation of group I metabotropic glutamate receptors signaling though the Fragile X Mental Retardation Protein (FMRP) pathway may underlie synaptic plasticity associated with aggression escalation. Female hamsters were given 5 daily aggression tests with or without prior treatment with the mGluR5 antagonist MPEP. Following aggression testing, mRNA expression and protein levels were measured in the nucleus accumbens for PSD-95 and SAPAP-3, as well as the levels of phosphorylated FMRP. Experience-dependent escalation of aggression in female hamsters depends on activation of mGluR5 receptors. Furthermore, aggressive experience decreases phosphorylation of FMRP in the NAc which is coupled to a long-term increase in the expression of the synaptic scaffolding proteins, PSD-95 and SAPAP-3. Finally, the experience-dependent increase in PSD-95 is prevented by antagonism of the mGluR5 receptor. Activation of the FMRP pathway by group I metabotropic glutamate receptors is involved in regulating synaptic plasticity following aggressive experience. The NAc is a novel target for preclinical studies of the treatment of escalated aggression, with the added benefit that emerging therapeutic approaches are likely to be effective in treating pathological aggression in both females and males.